Fertility in Cancer Patients can be Improved by New Technique

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A critical first step in the eventual development of a technique to retain fertility in women with cancer who require treatments that might otherwise make them unable to have children has been completed by researchers funded by the National Institutes of Health.

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The researchers have developed a method to advance undeveloped human eggs to near maturity, in laboratory cultures maintained outside the body. The technique focuses on the follicle, a tiny sac within the ovary that contains the immature egg. The researchers were able to grow human follicles in the laboratory for 30 days, until the eggs they contained were nearly mature.

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The research seeks to provide women who require a fertility-ending treatment with options for reproduction after their treatment is complete. Men facing such treatments can freeze their sperm for use at a later date. Female cancer patients have fewer options. Unlike sperm, eggs rarely survive freezing and thawing.

The accomplishment represents the successful completion of the first of three steps needed to preserve a woman's fertility after radiation treatments or chemotherapy. For the next step, researchers will need to induce the egg's final division, so that it contains only half the genetic material of its precursors. Finally, the researchers will have to demonstrate that they can freeze and thaw human follicles before growing them in culture.

"The new technique could provide an option for women and girls who have cancer and are not yet ready to start families," said Duane Alexander, M.D., director of NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), which funded the research as part of the NIH Roadmap Interdisciplinary Research Consortium program. "An additional benefit is that it will allow researchers to more closely follow the process by which immature eggs grow and mature. In turn, these observations may lead to new advances for treating other forms of infertility."

The best option currently for a female cancer patient to preserve fertility is to collect eggs, fertilize them with sperm, and freeze the resulting embryos. But that technique may not be acceptable to all female cancer patients.

Researchers have already identified experimental methods to freeze entire ovaries or strips of ovarian tissue and implant them in a woman's body when she is ready to have children. This is a good option for some patients, but it is possible that some cancer cells may hitch hike on the ovarian tissue and result in a new cancer after treatment is completed.

Developed by Teresa K. Woodruff, Ph.D. and Lonnie D. Shea, Ph.D., of Northwestern University's Feinberg School of Medicine, and their colleagues, the new technique would avoid both concerns.

The findings were published online in Human Reproduction.

The new findings build on earlier efforts by the research team, who grew mouse follicles in culture, induced the eggs they contained to mature, fertilized them with mouse sperm, and implanted them into female mice to establish pregnancy. The earlier research is described in an article that appeared in The NIH Record, at http://nihrecord.od.nih.gov/newsletters/2006/09_08_2006/story02.htm.

The researchers made the new advance by suspending the human follicle in a three-dimensional matrix of a gel-like material. They then flushed the follicle with the same hormones and growth factors that the follicle would be exposed to inside a woman's body.

In previous attempts to grow follicles, researchers had set the follicles on a flat surface, which the study authors now believe does not mimic closely enough conditions inside the body. These earlier attempts failed to develop good quality eggs that were healthy enough for fertilization.

For the current study, the researchers started with so-called secondary follicles, which are at an intermediate stage of development. They collected them from the ovarian tissue of 14 cancer patients.

During the 30-day experiment, the follicle grew and produced hormones and the immature egg matured just as it would inside a woman's body. The researchers found that the follicles would grow if injected into a gelatin mixture. The gelatin (called alginate) provided three-dimensional support for the follicle, much like the support it receives inside the body.

"The researchers have demonstrated that the technique produces healthy eggs," said Charisee Lamar, Ph.D., M.P.H., R.R.T., director of the Fertility Preservation Program in NICHD's Reproductive Sciences Branch. "The next step would be to investigate the viability of follicles from frozen tissue."

Another component of the NICHD program is attempting to grow follicles of monkeys in culture. The ability to do research on mouse and monkey follicles might lead to advances that could later be used to perfect the technique's use with human eggs.

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